Mitochondrial-Derived Oxidants and Cellular Responses to Low Dose/Low LET Ionizing Radiation

Abstract

Oxidants and Cellular Responses to Low Dose/Low LET Ionizing Radiation"; Spitz, Douglas R. (Principal Investigator), 05/15/05 -12/31/09 A. Progress Report: The objective during the last period of support (5/15/05-12/31/09) was to determine the involvement of mitochondrial genetic defects in metabolic oxidative stress and the biological effects of low dose/low LET radiation. Aim 1 was to determine if cells with mutations in succinate dehydrogenase (SDH) subunits C and D (SDHC and SDHD in mitochondrial complex II) demonstrated increases in steady-state levels of reactive oxygen species (ROS; O 2 -and H 2 O 2 ) as well as demonstrating increased sensitivity to low dose/low LET radiation (10 cGy) in vitro. Aim #2 was to determine if specific mitochondrially-derived ROS contributed to increased sensitivity to low dose/low LET radiation in cells containing mutations in SDH subunits in vitro. Aim #3 was to determine if a causal relationship existed between persistent increases in mitochondrial ROS production, alterations in electron transport chain proteins, and genomic instability in the progeny of irradiated cells.Progress in Aim #1 and #2 included the isolation and characterization of SDHC and SDHD mutants in Chinese hamster fibroblasts that were found to demonstrate increased steady-state levels of O 2 -, H 2 O 2 as well as genomic instability (1, 2). The cells expressing SDHC mutations showed 3-fold increases steady-state levels of O 2 -